Epidemiology and control of malaria (with a focus on sub-Saharan Africa) Grant Dorsey, MD, PhD Division of Infectious Diseases University of California, San Francisco

Burden of Disease Over 40% of the world’s population live in endemic areas Estimated 500 million clinical cases and 1-2 million deaths/year 3rd most common cause of death due to a communicable agent

Annual malaria mortality rates per 100,000 population since 1900

Burden of Malaria in Africa One African child dies of malaria every 30 seconds Higher in poor and rural areas In all malaria-endemic countries in Africa, malaria accounts for 25-40% of outpatient visits and 20-50% of hospital admissions

Malaria mortality in African children

Unique Epidemiological Aspects of Malaria in Africa Infection is incredibly common and heterogeneous High density of mosquitoes Mosquitoes like to bite humans and live indoors Very little vector control in Africa Gold standard for measuring the frequency of infection is termed the entomological inoculation rate (EIR) EIR = number of bites by anopheles mosquito per night x proportion of mosquitoes carrying malaria parasites in their salivary glands x 365 days per year

Unique Epidemiological Aspects of Malaria in Africa cont. Clinical consequences of infection vary greatly Disease manifestations range from asymptomatic parasitemia to life-threatening illness Risk of illness and death strongly influenced by development of “semi-immunity” over one’s lifetime High risk groups include young children, pregnant women, HIV-infected patients, and non-immune adults (i.e. travelers)

Estimating risk of infection, disease, and death ~ 50 billion infections with malaria parasites each year in Africa ~ 1:100 infections leads to clinical illness = 500 million cases of malaria each year ~ 1:50 cases of malaria results in the severe form of disease = 10 million cases of severe malaria each year ~ 1:5 cases of severe malaria leads to death = 1-2 million deaths due to malaria each year

Transmission intensity, incidence, and age Dielmo, Senegal – 200 infections/year Ndiop, Senegal – 20 infections/year

In the 20th century, the boundary of malaria transmission was progressively rolled back from the north Elimination < 1960 Elimination 1960 - 1975 Elimination 1975 - 2007 Elimination program ongoing Elimination newly targeted

Countries targeting elimination do not currently spend more per population at risk than some control programs… Estimated annual malaria financing per population at risk1 ~$22 Funding Source International2 Domestic $4.43 $3.17 $2.41 $2.53 $0.91 $0.19 DR Congo South Africa Swaziland Tanzania (mainland) Botswana Zambia UAE 1 Estimated based on Mapping Malaria Risk in Africa project updated for 2007 population levels 2 Includes funding allocations by the Global Fund, World Bank, and US President’s Malaria Initiative

…but do spend significantly more per case, which will continue to increase as incidence declines further Estimated annual malaria financing per case1 >$10m $200,000 $40 $800 $10.74 $5.76 $0.36 DR Congo Tanzania (mainland) Zambia Botswana South Africa UAE2 Oman2 1 Includes both reported and unconfirmed cases as estimated by the national program and/or partners 2 Based on 2003 estimates

Available tools for the control and elimination of malaria 1. Effective case management 2. Insecticide treated bednets (ITNs) 3. Vector control 4. Chemoprevention 5. Vaccine

Effective case management in the era of ACTs ACT’s have now become the standard of care throughout the world Artesunate+mefloquine Artemether-lumefantrine Artesunate+amodiaquine Dihydroartemisinin-piperaquine Excellent efficacy unless resistance to partner drug Early reports of artemisinin resistance in Thai-Cambodia border May decrease transmission through anti-gametocyte effects Concern about drug availability and cost

Effective case management Issues in resource poor settings Government recommends one first-line therapy for the whole country Policy based on clinical surveillance studies Drug subsidized for the public sector ACTs currently too expensive in the private sector Most fevers are treated empirically as malaria at home Urgent need to promote rationale use of ACTs

Joint malaria training program Objective: To evaluate the impact of integrated team-based training of health care workers on malaria case management. Design and Participants: Malaria surveillance data 120 days before and after training were compared for all patients presenting to eight government-run health centers. Setting: The eight sites represent the diversity of malaria transmission in Uganda. Data were collected one year after artemether-lumefantrine was introduced as the recommended first-line treatment for uncomplicated malaria. Intervention: Six day integrated team-based training course targeting clinical, laboratory and records staff with site visits approximately 6 and 12 weeks post training.

Proportion of patients suspected of having malaria referred for a blood smear

Proportion of patients with a positive blood smear treated for malaria

Proportion of patients with a negative blood smear treated for malaria

Proportion of patient prescribed antimalarial therapy who were given a correct regimen

Insecticide treated bednets (ITNs) Several randomized trials in a range of endemic settings have documented the efficacy of ITNs Interventions done at the population level ~ 10 fold reduction in transmission ~ 2 fold decrease in incidence of clinical malaria ~ 20% reduction in all cause childhood mortality One of the most cost effective interventions available Bednets cost only a few dollars Long lasting ITNs Insecticide impregnated into nets Last 5 years Remaining issues are coverage and distribution

Vector control Primary tool indoor residual spraying (IRS) Very effective in low transmission areas Starting to be used in higher transmission settings in Africa Limited data on what is the best insecticide and how often to spray Very expensive Other vector control measures Larvicide Genetically modified mosquitoes

IRS in moderate endemic setting in Uganda

Chemoprevention Two main strategies Target groups Chemoprophylaxis Intermittent preventative therapy Target groups Pregnant women HIV infected patients Daily trimethoprim-sulfamethoxazole Infants and young children Active area of research

Summary of studies evaluating IPTi with SP given at the time of routine immunizations Study parameter Country and year(s) of recruitment Tanzania 1999-00 Ghana 2000-02 Mozambique 2002-04 2003 2004 Gabon 2002-05 EIR*/year Transmission Age at dosing, months Incidence in placebo group† # enrolled, placebo/intervention Preventive efficacy, % (95% CI) Clinical malaria Hospital admission Anemia 29 Perennial 2, 3, 9 0.36 351/350 at 12 mo. 62 (44-75) 30 (8-47) 50 (8-73) 418 Seasonal 3, 4, 9, 12 1.02 1242/1243 at 15 mo. 25 (14-34) 13 (-5-27) 36 (11-53) 38 3, 4, 9 0.43 755/748 23 (2-39) 19 (4-31) 13 (-17-35) not reported 3, 9, 15 1.16 600/600 at 18 mo. 23 (12-32) 31 (3-51) 24 (4-39) 400 1.20 535/535 20 (11-29) 9 (-23-34) 7 (-8-20) 50 0.16 595/594 At 18 mo. 17 (-24-44) 22 (-1-40)

Control of Malaria in Africa cont. Vaccines 1973 vaccine made from whole malaria parasites killed by irradiation could protect healthy persons from infection Not a viable option for large scale production Decades of research failed to develop an effective vaccine Limited understanding of immune correlates of protection Organism extremely diverse and complicated Recent vaccine trials RTS,S vaccine Surface protein found in form of parasite injected by mosquitoes conjugated to Hep B surface Ag Pilot study in 360 Gambian men: 34% efficacy in protecting against malaria infection but waned to 0% by 15 weeks 1500 children in Mozambique: 30% reduction in clinical malaria and 58% reduction in severe malaria after 6 months Plans for large phase III trial underway

Success Story in South Africa Area of low seasonal transmission in setting of highly competent national malaria control program Wide scale implementation of IRS (A+B) and AL (C)